Idiopathic pulmonary fibrosis (IPF) is one of the most pernicious forms of lung fibrogenesis and currently has no clearly effective treatments. Whereas the etiology of IPF remains enigmatic, there is evidence of dysregulations of several major molecular pathways in lung fibroblasts of IPF patients, including apoptosis/survival pathways as well as TGF-, Akt, and MAPK signaling. In our preliminary studies, we found that the expression of miR-21 is upregulated in the lungs of mice with bleomycin-induced lung fibrosis and in the lungs of patients with IPF. Target predictions as well as previous studies demonstrate that miR-21 regulates the expression of PDCD4, Smad7, Spry1, and PTEN. These proteins are critical negative regulators of cell proliferation and survival as well as TGF-, PI3K, and MAPK signaling. This information, together with our preliminary data, suggests that miR-21 may play an important role as an integrator in initiation and progression of IPF. Therefore, miR-21 appears to be a potential target for developing novel therapeutics to treat IPF. Our preliminary data showing that sequestering miR-21 by anti-miR-21 probes diminishes the severity of bleomycin induced lung fibrosis lend a strong support to this hypothesis. In this proposal, we aim to 1) characterize miR-21 expression in human lung fibroblasts, in the lungs of mice with bleomycin induced pulmonary fibrosis and in the lungs of patients with IPF; 2) delineate the role of miR-21 in vivo during bleomycin induced lung fibrosis; 3) delineate the mechanisms by which miR-21 regulates lung fibrosis; 4) delineate the role of miR-21 in modulating the ex vivo pathological properties of lung fibroblasts from IPF patients.